Science Weekly: Lift off for the UK Space Agency

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Quantum information, the UK’s very own Nasa, the Templeton prize controversy and a rainforest at London Zoo

Growth at Target Health

Target Health is pleased to announce that as a small business, we are contributing to the overall recovery of the US economy. If every small business followed our path, the recession would be over. Over the past 6 months, we have added five jobs and we are still hiring. Three of the positions were in Clinical Research where we have added 2 project managers and one Sr. CRA. With the layoffs in Big Pharma, we were able to get very experienced people from Wyeth, Merck and a device company. We also hired a top web programmer who will strengthen our software development group, as well as a data manager. Target Health is a privately held business with no investors and no debt. In today’s economy, this conservative business approach allows us to optimize our client services and at the same time provide stability to our dedicated staff.

For more information about Target Health and our software tools for paperless clinical trials, please contact Warren Pearlson (212-681-2100 ext 104) or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health website at: www.targethealth.com

Kidney Disease Hides in People with Undiagnosed Diabetes

Millions of Americans may have chronic kidney disease (CKD) and not know it, according to a study appearing in an upcoming issue of the Clinical Journal of the American Society Nephrology (CJASN). “Our research indicates that much of the CKD burden in the US is in persons with prediabetes and undiagnosed 1) ___, who are not being screened for CKD,“ said Laura C. Plantinga, ScM (University of California, San Francisco). The researchers believe that broader 2) ___ may be needed to detect patients with these two relatively silent yet harmful diseases. The study analyzed a nationally representative sample of about 8,200 Americans from the National Health and Nutrition Examination Survey. Standard laboratory tests were used to assess the rate of CKD, focusing on people with undiagnosed diabetes or prediabetes (sometimes called 3) ___ diabetes). Based on laboratory tests, 42% of subjects with undiagnosed diabetes had CKD – similar to the 40% rate in those with diagnosed diabetes. Only a small percentage of participants were aware of the 4) ___ of CKD. In addition, CKD was present in nearly 18% of subjects with prediabetes. Among participants without diabetes or prediabetes, the rate of CKD was about 11%. According to the authors, there may be a substantial number of individuals in the US – up to 13 million – who have undiagnosed diabetes or prediabetes and who already have 5) ___ of kidney damage and/or reduced kidney function. Such patients would be at high risk for worsening kidney disease and diabetes, and for the poor outcomes associated with both conditions – including 6) ___ disease and death. Diabetes is the most important risk factor for kidney disease, but the new results suggest that harmful effects on the kidneys may be occurring even before diabetes is diagnosed. Persons at 7) ___ for diabetes and their health care providers should be aware that earlier screening for both diabetes and kidney disease may be warranted. Earlier screening would allow for appropriate, timely medical care to prevent further progression and poor outcomes. Although the study shows an association, it cannot determine whether the development of CKD followed the development of diabetes, or whether CKD was actually caused by diabetes.

ANSWERS: 1) diabetes; 2) screening; 3) “borderline” 4) diagnosis; 5) signs; 6) cardiovascular; 7) risk

Hans Adolf Krebs – 1900-1981

Sir Hans Adolf Krebs was a German Jewish born British physician and biochemist. Krebs is best known for his identification of two important metabolic cycles: the urea cycle and the citric acid cycle. The latter, the key sequence of metabolic chemical reactions that produces energy in cells, is also known as the Krebs cycle and earned him a Nobel Prize in 1953. Krebs was born in Hildesheim, Germany, to Georg Krebs, an ear, nose, and throat surgeon, and Alma Davidson . He went to school in Hildesheim and studied medicine at the University of Goettingen and at the University of Freiburg from 1918-1923. He earned his Ph.D. at the University of Hamburg in 1925. He then studied chemistry in Berlin for one year, where he later became an assistant of Otto Warburg at the Kaiser Wilhelm Institute for Biology until 1930. Krebs joined the German army in 1932, and was appointed to the 13th mechanized infantry division in spite of his Jewish faith. Krebs returned to clinical medicine at the municipal hospital of Altona and then at the medical clinic of the University of Freiburg, where he conducted research and discovered the urea cycle. Because he was Jewish, Krebs was barred from practicing medicine in Germany and he emigrated to England in 1933. There he was invited to Cambridge, where he worked in the biochemistry department under Sir Frederick Gowland Hopkins (1861-1947). Krebs became professor of biochemistry at the University of Sheffield in 1945. Krebs’s area of interest was intermediary metabolism. He identified the urea cycle in 1932, and the citric acid cycle in 1937 at the University of Sheffield. He moved to Oxford as Professor of Biochemistry in 1954 and after his retirement continued work at the Radcliffe Infirmary, Oxford until his death. In 1953 he received the Nobel Prize in Physiology for his discovery of the citric acid cycle and was knighted in 1958. In short, the Krebs cycle constitutes the discovery of the major source of energy in all living organisms. Within the Krebs cycle, energy in the form of ATP is usually derived from the breakdown of glucose, although fats and proteins can also be utilized as energy sources. Since glucose can pass through cell membranes, it transports energy from one part of the body to another. The Krebs cycle affects all types of life and is, as such, the metabolic pathway within the cells. This pathway chemically converts carbohydrates, fats, and proteins into carbon dioxide, and converts water into serviceable energy. The Krebs cycle is involved in the second of three major stages every living cell must undergo in order to produce energy, which it needs in order to survive. The enzymes that cause each step of the process to occur are all located in the cell’s “power plant.“ In animals, this is the mitochondria; in plants, it is the chloroplasts; and in microorganisms, it can be found in the cell membrane. The Krebs cycle is also known as the citric acid cycle, because citric acid is the very first product generated by this sequence of chemical conversions.

VIROLOGY

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1918 and 2009 Pandemic Influenza Viruses Lack a Sugar Topping

According to an article published online in Science Translational Medicine 2010; (DOI: 10.1126/scitranslmed.3000799), the influenza viruses responsible for the pandemics of 1918 and 2009 share a structural detail that makes both susceptible to neutralization by the same antibodies. The molecular basis for this shared vulnerability suggests how it might be exploited to design vaccines matched to future pandemic-influenza virus strains. In one set of experiments, mice were injected with a vaccine made from inactivated 1918 influenza virus. Then the mice were exposed to high levels of 2009 H1N1 virus. All of the vaccinated mice survived. The reverse was also true: Mice vaccinated with inactivated 2009 H1N1 virus and then exposed to 1918 virus were protected from death. The authors concluded that vaccination with either pandemic virus caused the mice to produce antibodies capable of neutralizing the other virus. Ordinarily, antibodies made in response to one year’s seasonal flu strain do not fully react with, or cross-neutralize, seasonal flu strains that come along just a few years later. This is due in part to slight, yearly changes in the amino acid sequence of hemagglutinin (HA), a viral surface protein. The amino acid sequences of the 1918 and 2009 H1N1 influenza viruses in a portion of HA called the globular head differ by about 20%. That difference is on a par with amino acid divergence in the HA head region among seasonal strains. Therefore, the authors reasoned that antibody cross-neutralization in the pandemic viruses must be due to some feature besides simply the degree of amino acid variation. In a series of experiments and computer modeling studies, it was determined that both pandemic viruses lack a cap of sugar (glycan) molecules at two specific spots on the top of HA’s globular head.  Without these sugars, both the 1918 and 2009 pandemic viruses have unfettered access to the receptors that HA uses to enter human cells. This viral advantage quickly diminishes as immunity provided by neutralizing antibodies arises in people who have been infected (and recovered) or when people are vaccinated. In contrast to the 1918 and 2009 viruses, when the authors analyzed the structure of seasonal flu strains that had circulated between 1977 and 2008, they found that 97.8% had one glycan molecule covering the HA’s head, while 87.8% of the strains had two glycans. The authors stated that “The glycans act like an umbrella that shields the virus from the immune system,” and “they create a physical barrier over the virus and prevent antibody neutralization.” Further analysis of influenza sequences collected prior to 1977 revealed that the HA protein in the descendants of the 1918 influenza virus acquired glycans by the early 1940’s. Next, the Authors engineered mutant pandemic flu viruses by placing sugar molecules on the two critical regions at the top of the globular head. Once covered, antibodies could no longer recognize and neutralize the virus. However, the sugar-capped viruses did perform well as vaccines. In the last series of experiments, the investigators added sugar molecules to a 1918 influenza virus and vaccinated mice with it. The mice produced antibodies able to neutralize the original, sugar-free version of the 1918 virus. According to the authors, “We can use this knowledge to preemptively design vaccines with glycosylated versions of the newly emerged 2009 H1N1 pandemic influenza virus,” and “such a vaccine, would protect against the pandemic virus and might also limit the virus’s chances of acquiring a sugar shield that would allow it to entrench itself as a seasonal variant.

VIROLOGY

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Rapid Development of Drug-Resistant 2009 H1N1 Influenza Reported in Two Cases

The 2009 H1N1 influenza virus is susceptible to just one of the two available classes of anti-influenza drugs, the neuraminidase inhibitors. Besides oseltamivir, other neuraminidase inhibitors are zanamivir (Relenza), which is inhaled, and the intravenously administered investigational drug peramivir. As the H1N1 influenza pandemic unfolded, laboratory tests of virus strains isolated from patients showed that some strains contained a genetic mutation (the H275Y mutation) that makes the virus less susceptible to some neuraminidase inhibitors. According to an article published online in Clinical Infectious Diseases (26March2010), 2 people with compromised immune systems who became ill with 2009 H1N1 influenza developed drug-resistant strains of virus after less than two weeks on therapy. NIH cautioned that doctors who treat prolonged influenza infection should be aware that even a short course of antiviral treatment may lead to drug-resistant virus, and clinicians should consider this possibility as they develop initial treatment strategies for their patients who have impaired immune function. Both patients described in the new report developed resistance to the key influenza drug oseltamivir (Tamiflu), and one also demonstrated clinical resistance to another antiviral agent, now in experimental testing, intravenous peramivir. This is the first reported case of clinically significant peramivir-resistant 2009 H1N1 illness. The 2 people in the current case report had immune limitations due to blood stem cell transplants that occurred several years previously. Both recovered from their influenza infections. Both people in the current case study had pre-existing medical conditions that impaired their immune system function before contracting 2009 H1N1 flu. Strains of 2009 H1N1 influenza containing the H275Y mutation had been reported previously in people with diminished immune function, but in previous cases the mutation arose after more than 24 days of continuous therapy. In the newly described cases, the mutation appeared after 14 days in one individual and after nine days in the second. Both people received oseltamivir for extended periods but they continued to shed virus in their nasal secretions throughout treatment. When one patient’s condition worsened despite 24 days of oseltamivir treatment, doctors administered peramivir for 10 days. The drug did not reduce viral shedding and the patient remained ill, demonstrating what the authors described as clinically significant resistance to peramivir. Next, doctors administered the only other available flu drug, zanamivir, for 10 days. The person then fully recovered. The mutation that allows 2009 H1N1 to resist oseltamivir also significantly reduces the virus’s susceptibility to peramivir. If a relatively short course of oseltamivir causes a mutant flu strain to emerge in a particular patient, that person may not respond to peramivir. Zanamivir might be a good choice if a patient does not respond within a few days to oseltamivir. However, because zanamivir must be inhaled, patients who are very ill and whose breathing is mechanically supported cannot be given zanamivir.

Physical Activity and Weight Gain Prevention

While the amount of physical activity needed to prevent long-term weight gain is unclear, in 2008, federal guidelines recommended at least 150 minutes per week (7.5 metabolic equivalent [MET] hours per week) of moderate-intensity activity for “substantial health benefits.“ As a result, a study published in the Journal of the American Medical Association (2010;303:1173-1179), was performed to examine the association of different amounts of physical activity with long-term weight changes among women consuming a usual diet. The investigation was a prospective cohort study involving 34,079 healthy US women (mean age, 54.2 years) from 1992-2007. At baseline and years 3, 6, 8, 10, 12, and 13, women reported their physical activity and body weight. Women were classified as expending less than 7.5, 7.5 to less than 21, and 21 or more MET hours per week of activity at each time. Repeated-measures regression prospectively examined physical activity and weight change over intervals averaging 3 years. The main outcome measure was change in weight. Results showed that women gained a mean of 2.6 kg throughout the study. A multivariate analysis comparing women expending 21 or more MET hours per week with those expending from 7.5 to less than 21 MET hours per week showed that the latter group gained an average of 0.11 kg (P = .003) over a mean interval of 3 years, and those expending less than 7.5 MET hours per week gained 0.12 kg (P = .002). There was a significant interaction with body mass index (BMI), such that there was an inverse dose-response relation between activity levels and weight gain among women with a BMI of less than 25 (P for trend < .001) but no relation among women with a BMI from 25 to 29.9 or with a BMI of 30.0 or higher. A total of 4,540 women (13.3%) with a BMI lower than 25 at study start successfully maintained their weight by gaining less than 2.3 kg throughout the study. Their mean activity level over the study was 21.5 MET hours per week (60 minutes a day of moderate-intensity activity). According to the authors, among women consuming a usual diet, physical activity was associated with less weight gain only among women whose BMI was lower than 25 and that women, successful in maintaining normal weight and gaining fewer than 2.3 kg over 13 years, averaged approximately 60 minutes a day of moderate-intensity activity throughout the study.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

FDA Approves Orphan Drug to Treat Condition That Causes Elevated Ammonia Levels

The FDA has approved Carbaglu (carglumic acid) Tablets to treat a condition that results in too much ammonia in the blood. The condition, N-acetylglutamate synthase or NAGS deficiency, is an extremely rare, genetic disorder that can be present in babies soon after birth. NAGS deficiency and the resulting elevated levels of ammonia (hyperammonemia) can be fatal if it is not detected and treated rapidly. DNA testing can confirm the diagnosis of NAGS. The safety and efficacy of Carbaglu was studied in 23 patients with NAGS who received the treatment for times ranging from six months to 21 years. In these patients, Carbaglu reduced blood ammonia levels within 24 hours and normalized ammonia levels within three days. The majority of those in the study appeared to maintain normal plasma ammonia levels with long-term Carbaglu treatment. Side effects experienced by those using Carbaglu included vomiting, abdominal pain, fever, tonsillitis, anemia, ear infection, diarrhea, inflammation of the nose and throat, and headache. As with all FDA-approved products, the agency will continue to monitor Carbaglu as it is used to treat hyperammonemia. Carbaglu should only be administered by a physician experienced in treating metabolic disorders. The recommended initial dose of Carbaglu is 100 to 250 mg/kg/day for treatment of acute hyperammonemia. Use of other ammonia-lowering therapies with Carbaglu during episodes of acute hyperammonemia is recommended. Dosing should be adjusted based on a patient’s ammonia levels and symptoms.

For more information about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development.

Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, Management of Clinical Trials, Biostatistics, Data Management, EDC utilizing Target e*CRF®, Project Management, and Medical Writing.

 Target Health has developed a full suite of eClinical Trial software including 1) Target e*CRF® (EDC plus randomization and batch edit checks), 2) Target e*CTMS™, 3) Target Document®, 4) Target Encoder®, 5) Target Newsletter®, 6) Target e*CTR™ (electronic medical record for clinical trials).

Target Health ‘s Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.

 


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